Inhibition of protective immunity against Staphylococcus aureus infection by MHC-restricted immunodominance is overcome by vaccination

Abstract

Recurrent Staphylococcus aureus infections are common, despite robust immune responses. S. aureus infection elicited protective antibody and T cell responses in mice that expressed the Major Histocompatibility Complex (MHC) of the H-2d haplotype, but not H-2b, demonstrating that host genetics drives individual variability. Vaccination with a-toxin or leukotoxin E (LukE) elicited similar antibody and T cell responses in mice expressing H-2d or H-2b, but vaccine-elicited responses were inhibited by concomitant infection in H-2d–expressing mice. These findings suggested that competitive binding of microbial peptides to host MHC proteins determines the specificity of the immunodominant response, which was confirmed using LukE-derived peptide-MHC tetramers. A vaccine that elicited T cell and antibody responses protected mice that expressed H-2d or H-2b, demonstrating that vaccination can overcome MHC-restricted immunodominance. Together, these results define how host genetics determine whether immunity elicted by S. aureus is protective and provide a mechanistic roadmap for future vaccine design.

Virulence Factors in Coagulase-Negative Staphylococci

“…By analyzing all failed attempts, it became clear that targeting a single antigen has limited success and, thus, a multivalent approach would increase the chances of developing effective vaccines. Hence, new advances were made in the past few years, reviving the interest in developing vaccines against infections caused by staphylococcal species [507,520].…”

Evasion of Immunological Memory by S. aureus Infection: Implications for Vaccine Design

“…Unfortunately, epitopes that are ImD in driving B cell/antibody responses are not necessarily the same epitope that drive ImD T cell responses. A variety of ImD T cell epitopes have been identified in animal models, including epitopes within a phosphodiesterase (Plc) ( 49 ), LukE and LukS-PV ( 50 ), nuclease ( 51 ), and IsdB ( 52 ), and clumping factor A and protein A appear to elicit T cell responses in both mice and humans ( 53 , 54 ). However, unlike antibody responses, a relative hierarachy for T cell antigens/epitopes has not been established.…”

“…Mouse models have uncovered one possible mechanistic explanation for these observations. BALB/c mice are protected against secondary SSTI, but C57BL/6 mice are not ( 50 ). These divergent phenotypes were explained by the different MHC class II haplotypes in the mouse strains: BALB/c mice express MHC H-2 d and C57BL/6 express H-2 b ( 50 ).…”

“…BALB/c mice are protected against secondary SSTI, but C57BL/6 mice are not ( 50 ). These divergent phenotypes were explained by the different MHC class II haplotypes in the mouse strains: BALB/c mice express MHC H-2 d and C57BL/6 express H-2 b ( 50 ). In this model, antibody responses against Hla and Th17 responses against LukE and LukS-PV were observed only in mice that express MHC H-2 d .…”

“…Moreover, concomitant infection inhibited vaccine efficacy in C57BL/6 mice, but not BALB/c mice. The mechanism of this inhibition was due to strong binding of protective epitopes to MHC H-2 d , but not H-2 b ( 50 ). Based on these findings, a model emerges of competition between different staphylococcal antigens for binding to MHC proteins, and ImD antigens are more successful in this competition.…”